This invention relates to substituted (aminoiminomethyl or aminomethyl) dihydrobenzofurans and benzopyrans that inhibit Factor Xa, pharmaceutical compositions comprising these compounds and their use for inhibiting Factor Xa or treating pathological conditions in a patient that may be ameliorated by administration of such compounds. This invention also relates to substituted (aminoiminomethyl or aminomethyl) dihydrobenzo-furans and benzopyrans which directly inhibit both Factor Xa and Factor IIa (thrombin), to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds and to a method of simultaneously directly inhibiting both Factor Xa and Factor IIa (thrombin).
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Moreover, Factor Xa inhibition is effected by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective Factor Xa inhibition is achieved by administering the compounds either orally, by continuous intravenous infusion, by bolus intravenous administration or by any other parenteral route such that it achieves the desired effect of inhibiting physiological events mediated by the catalytic activity of Factor Xa.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting (CABG) of the coronary or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors, resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems.
Accumulated experimental evidence has also indicated that prothrombin activation is only one of the biological activities of Factor Xa. For example, Factor Xa is believed to influence several vascular wall phenomena by interaction with EPR-1 (effector cell protease receptor-1, which recognizes Factor Xa). EPR-1 has been shown to be expressed on human umbilical vein endothelial cells, rat smooth muscle cells and platelets (C R McKenzie, et al., Arterioscler Thromb Vasc Biol 16 1285-91 (1996); F Bono, et al., J Cell Physiol 172 36-43 (1997); A C Nicholson, et al., J Biol Chem 271 28407-13 (1996); and J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). This protease-receptor interaction could mediate not only prothrombinase-catalyzed thrombin generation, but also diverse cellular functions such as cell proliferation, release of PDGF and DNA syntheses. The mitogenic effect of Factor Xa has been reported to be dependent on Factor Xa enzymatic activity (F Bono, et al., J Cell Physiol 172 36-43 (1997); and J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). TAP, for example, inhibited the mitogenesis of human and rat cultured vascular smooth muscle cells (F Bono, et al., J Cell Physiol 172 36-43 (1997)). In a study of the rabbit carotid artery air-drying injury model, increased EPR-1 expression was detected after vascular injury. Animals treated with the specific Factor Xa inhibitor, DX-9065a, exhibited less neointimal proliferation. The important regulatory role of Factor Xa in the coagulation process coupled with its mitogenic effects points to Factor Xa""s involvement in the formation of thrombin at the luminal surface of the vessel wall and contribution to the atherothrombotic process and abnormal proliferation of vascular cells resulting in restenosis or angiogenesis.
Vascular injury caused by biochemical or physical perturbations, results in the activation of the coagulation system, culminating in the generation of thrombin. Thrombin promotes thrombus formation by catalyzing the transformation of fibrinogen to fibrin, by activating Coagulation Factor XIII that stabilizes the thrombus, and by activating platelets. Thrombin promotes further thrombus growth by positive feedback to the coagulation cascade (activation of Coagulation Factors V and VIII), resulting in the explosive production of thrombin. Thrombin is present, and active, in the thrombi of patients with thrombotic vascular disease. Thrombin inhibition prevents the action of thrombin after thrombin has been activated from prothrombin. An inhibitor of thrombin inhibits cleavage of fibrinogen to fibrin, activation of Factor XIIIa, activation of platelets, and feedback of thrombin to the coagulation cascade to generate more thrombin. Consequently, inhibition of thrombin activity with a direct thrombin inhibitor would be useful for preventing or treating disorders related to blood coagulation in mammals.
The combined Xa/IIIa inhibitors described here inhibit thrombin activity (via IIa inhibition) and thrombin production (via Factor Xa inhibition). Therefore, these agents inhibit any thrombin that may be present and also inhibit the further production of thrombin. Other agents that have this dual activity include heparin and low molecular weight heparins (LMWHs), which have demonstrated efficacy in thrombotic diseases. However, heparin and LMWHs act indirectly through a cofactor, antithrombin-III (ATIII), to inhibit Xa and IIa. The heparin/ATIII complex is too large, however, to inhibit thrombus-bound Xa and IIa, thus limiting their efficacy. Direct inhibitors of Xa and IIa, as described here, are capable of inhibiting soluble and thrombus-bound Xa and IIa, thus providing an important therapeutic advantage over currently available Xa/IIa inhibitors.
In view of the physiological conditions discussed above related to Factor Xa, inhibitors of Factor Xa would be useful in treating those and other conditions that would be ameliorated by a Factor Xa inhibitor.
This invention is directed to a compound of formula I: 
n=1 or 2
W is H or a ring system substituent.
R is hydrogen, cyano, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroaryleycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, or fused heterocyclyiheteroaryl,
R1 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;
R2 and R3 are each hydrogen, or, taken together are xe2x95x90NR4;
R4 is hydrogen, R5O2Cxe2x80x94, R5Oxe2x80x94, HOxe2x80x94, cyano, R5COxe2x80x94, HCOxe2x80x94, lower alkyl, nitro, or R6R7N;
R5 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R6 and R7are independently hydrogen or alkyl;
L1 is alkylene, alkenylene or alkynylene;
L2 is absent (i.e. a chemical bond), alkylene, alkenylene, alkynylene, alkylene-Oxe2x80x94, alkenylene-Oxe2x80x94, alkynylene-Oxe2x80x94, alkylene-Sxe2x80x94, alkenylene-Sxe2x80x94, alkynylene-Sxe2x80x94, alkylene-S-alkylene, alkenylene-S-alkylene, alkynylene-S-alkylene, alkylene-O-alkylene, alkenylene-O-alkylene, alkynylene-O-alkylene, alkylene-C(O)xe2x80x94, alkenylene-C(O)xe2x80x94, alkynylene-C(O)xe2x80x94, provided that when L2 is absent, then R is not hydrogen, and Q is attached to R through a carbon atom thereof;
Q is xe2x80x94NR8xe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94NR8xe2x80x2C(X1)xe2x80x94, xe2x80x94C(X1)NR8xe2x80x2xe2x80x94,xe2x80x94NR8C(X1)Oxe2x80x94, xe2x80x94OC(X1)NR8xe2x80x94, xe2x80x94NR8C(X1)NR8xe2x80x94, xe2x80x94NR8C(X1)NR8xe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94NR8SO2xe2x80x94 or xe2x80x94SO2NR8xe2x80x94, provided that a nitrogen atom or oxygen atom of Q is not directly bonded to a carbon atom of L1 or L2 having a double bond or triple bond, or Qxe2x80x94L2xe2x80x94R is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, provided that a nitrogen atom or oxygen atom of Q is not directly bonded to a carbon atom of L1 having a double bond or triple bond;
X1 is O or S;
R8xe2x80x2 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl, heteroaroyl or alkoxycarbonyl;
R8 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl or heteroaroyl; and
m is 0, 1 or 2, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group that may be straight or branched-chain having about 1 to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 10 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means 1 to about 4 carbon atoms in the chain, which may be straight or branched. The alkyl may be substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d that may be the same or different, and include halo, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl Y1Y2Nxe2x80x94Y1Y2NCOxe2x80x94, Y1Y2NCONHxe2x80x94, Y1Y2NCO2xe2x80x94Y1Y2NSO2xe2x80x94, wherein Y1 and Y2 are independently hydrogen, alkyl, aryl, heteroaryl, alkoxyalkyl, hydroxyalkyl. Representative alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain having from 1 to about 10 carbon atoms. The preferred alkylene groups are the lower alkylene groups having from 1 to about 4 carbon atoms. The alkylene group may be substituted by one or more halo, hydroxy, acyl, alkoxycarbonyl aryl, heteroaryl or carboxy substitutent(s). Exemplary alkylene groups include methylene, ethylene, propylene and butylene; preferred is ethylene.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched-chain having 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 10 carbon atoms in the chain; and more preferably 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halo. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain having a double bond and from 2 to about 10 carbon atoms. Preferred alkenylene groups are the lower alkenylene groups having from 2 to about 4 carbon atoms. The alkenylene group may be substituted by one or more halo, hydroxy, acyl, alkoxycarbonyl alkoxycarbonyl, aryl, heteroaryl or carboxy substituents, provided that the hydroxy is not substituted at a carbon thereof having a double bond. Exemplary alkenylene groups include ethenylene, propenylene and butenylene.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched-chain having 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 10 carbon atoms in the chain, more preferably 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. xe2x80x9cLower alkynylxe2x80x9d means 2 to about 4 carbon atoms in the chain that may be straight or branched. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.
xe2x80x9cAlkynylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain having a carbon-carbon triple bond and from 2 to about 10 carbon atoms. Preferred alkynylene groups are the lower alkynylene groups having from 2 to about 4 carbon atoms. The alkynylene group may be substituted by one or more halo, hydroxy, acyl, alkoxycarbonyl aryl, heteroaryl or carboxy substituent(s), provided that the hydroxy is not substituted at a carbon thereof having a triple bond. Exemplary alkynylene groups include ethynylene, propynylene and butynylene.
xe2x80x9cChemical bondxe2x80x9d means a direct bond.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl ring system is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl groups include 1-decalin, norbornyl, adamantyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkylene rings contain about 5 to 6 ring atoms. The cycloalkenyl ring system is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cHeterocyclenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which system contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heterocyclenyl ring system is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl ring system is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Representative multicyclic oxaheterocyclenyl groups are 7-oxabicyclo[2.2.1]heptenyl and 4,5,6,7-tetrahydro-benzofuranyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like. A heterocyclenyl may also be a xe2x80x9clactamxe2x80x9d where the heterocyclenyl is an appropriately dioxo substituted azaheterocyclenyl, for example maleimide.
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system of 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heterocyclyl ring system is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d, which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic heterocyclyl rings include piperidyl; pyrrolidinyl; piperazinyl; morpholinyl; thiomorpholinyl; thiazolidinyl; 1,3-dioxolanyl; 1,4-dioxanyl; tetrahydrofuranyl; tetrahydrothiophenyl; tetrahydrothiopyranyl, [1,2]dithiolan, and the like. A heterocyclyl may also be a xe2x80x9clactamxe2x80x9d where the heterocyclyl is an appropriately dioxo substituted azaheterocyclyl, for example succinimide.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative aryl groups include phenyl, naphthyl, substituted phenyl and substituted naphthyl.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d, which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl; furanyl; thienyl; pyridyl; pyrimidinyl; isoxazolyl; isothiazolyl; oxazolyl; thiazolyl; pyrazolyl; furazanyl; pyrrolyl; pyrazolyl; triazolyl; 1,2,4-thiadiazolyl; pyrazinyl; pyridazinyl; quinoxalinyl; phthalazinyl; 1(2H)-phthalazinonyl; imidazo[1,2-a]pyridine; imidazo[2,1-b]thiazolyl; benzofurazanyl; indolyl; azaindolyl; benzimidazolyl; benzothienyl; quinolinyl; imidazolyl; thienopyridyl; quinazolinyl; thienopyrimidyl; pyrrolopyridyl; imidazopyridyl; isoquinolinyl; benzoazaindolyl; azabenzimidazolyl, 1,2,4-triazinyl; benzothiazolyl and the like.
xe2x80x9cFused arylcycloalkenylxe2x80x9d means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl contains about 5 to 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkenyl include 1,2-dihydronaphthylene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylarylxe2x80x9d means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylcycloalkylxe2x80x9d means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl contains about 5 to 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkyl include 1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylarylxe2x80x9d means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclenylxe2x80x9d means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl contains about 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused arylheterocyclenyl include 3H-indolinyl; 1H-2-oxoquinolyl; 2H-1-oxoisoquinolyl; 1,2-dihydroquinolinyl; 3,4-dihydroquinolinyl; 1,2-dihydroisoquinolinyl; 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclenylarylxe2x80x9d means a radical derived from a fused arylheterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclylxe2x80x9d means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl containing about 5 to 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative preferred fused arylheterocyclyl ring systems include phthalimide; 1,4-benzodioxane; indolinyl; 1,2,3,4-tetrahydroisoquinoline; 1,2,3,4-tetrahydroquinoline; 1H-2,3-dihydroisoindolyl; 2,3-dihydrobenz[f]isoindolyl; 1,2,3,4-tetrahydrobenz[g]isoquinolinyl, 1,3-benzodioxole, xanthene and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylarylxe2x80x9d means a radical derived from a fused arylheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom. A fused heterocyclylaryl may also be a xe2x80x9clactamxe2x80x9d where the heterocyclyl is an appropriately dioxo substituted azaheterocyclenyl, for example phthalimide.
xe2x80x9cFused heteroarylcycloalkenylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl; 5,6-dihydroisoquinolyl; 5,6-dihydroquinoxalinyl; 5,6-dihydroquinazolinyl; 4,5-dihydro-1H-benzimidazolyl; 4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylheteroarylxe2x80x9d means a radical derived from a fused heteroarylcycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroaylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylcycloalkylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof contains about 5 to 6 ring atoms and the cycloalkyl contains about 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyls include 5,6,7,8-tetrahydroquinolinyl; 5,6,7,8-tetrahydroisoquinolyl; 5,6,7,8-tetrahydroquinoxalinyl; 5,6,7,8-tetrahydroquinazolyl; 4,5,6,7-tetrahydro-1H-benzimidazolyl; 4,5,6,7-tetrahydrobenzoxazolyl; 1H-4-oxa-1,5-diazanaphthalen-2-only; 1,3-dihydroimidizole-[4,51-pyridin-2-onyl, 4,5,6,7-tetrahydro-benzo[c]thienyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylheteroarylxe2x80x9d means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclenylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof contains about 5 to 6 ring atoms and the heterocyclenyl contains about 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclenyl groups include 7,8-dihydro[1,7]naphthyridinyl; 1,2-dihydro[2,7]naphthyridinyl; 6,7-dihydro-3H-imidazo[4,5-c]pyridyl; 1,2-dihydro-1,5-naphthyridinyl; 1,2-dihydro-1,6-naphthyridinyl; 1,2-dihydro-1,7-naphthyridinyl; 1,2-dihydro-1,8-naphthyridinyl; 1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclenylheteroarylxe2x80x9d means a radical derived from a fused heteroarylheterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to 6 ring atoms and the heterocyclyl consists of about 5 to 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclyl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclyl include 2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl; 1,2,3,4-tetrahydrobenz [b][1,7]naphthyridin-2-yl; 1,2,3,4-tetrahydrobenz [b][1,6]naphthyridin-2-yl; 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl; 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl; 2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl; 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl; 1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl; 1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl; 5,6,7,8-tetrahydro[1,7]naphthyridinyl; 1,2,3,4-tetrhydro[2,7]naphthyridyl; 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl; 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl; 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl; 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl; 6,7-dihydro[5,8]diazanaphthalenyl; 1,2,3,4-tetrahydro[1,5] naphthyridinyl; 1,2,3,4-tetrahydro[1,6]naphthyridinyl; 1,2,3,4-tetrahydro[1,7]naphthyridinyl; 1,2,3,4-tetrahydro[1,8]naphthyridinyl; 1,2,3,4-tetrahydro[2,6]naphthyridinyl, xanthine and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylheteroarylxe2x80x9d means a radical derived from a fused heteroarylheterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heteroarylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl-group in which the aryl and alkyl are as defined herein. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenyl-group in which the aryl and alkenyl are as defined herein. Preferred aralkenyls contain a lower alkenyl moiety. Representative aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl.
xe2x80x9cAralkynylxe2x80x9d means an aryl-alkynyl-group in which the aryl and alkynyl are as defined herein. Preferred aralkynyls contain a lower alkynyl moiety. Representative aralkynyl groups include phenacetylenyl and naphthylacetylenyl.
xe2x80x9cHeteroaralkylxe2x80x9d means an heteroaryl-alkyl-group in which the heteroaryl and alkyl are as defined herein. Preferred heteroaralkyls contain a lower alkyl moiety. Representative aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl.
xe2x80x9cHeteroaralkenylxe2x80x9d means an heteroaryl-alkenyl-group in which the heteroaryl and alkenyl are as defined herein. Preferred heteroaralkenyls contain a lower alkenyl moiety. Representative heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl.
xe2x80x9cHeteroaralkynylxe2x80x9d means an heteroaryl-alkynyl-group in which the heteroaryl and alkynyl are as defined herein. Preferred heteroaralkynyls contain a lower alkynyl moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl and quinolin-3-ylacetylenyl.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl-group in which alkyl is as defined herein. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or an alkyl-COxe2x80x94 group in which the alkyl group is as defined herein. Preferred acyls contain a lower alkyl. Representative acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as defined herein. Representative groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-COxe2x80x94 group in which the heteroaryl group is as defined herein. Representative heteroaroyl groups include nicotinoyl, pyrrol-2-ylcarbonyl and 3-quinolincarbonyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as defined herein. Representative aryloxy groups include phenoxy and naphthoxy.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as defined herein. Representative heteroaryloxy groups include pyridyloxy and thienyloxy.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group in which the aralkyl group is as defined herein. Representative aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as defined herein. Representative alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as defined herein. Representative arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group in which the aralkyl group is as defined herein. A representative aralkylthio group is benzylthio.
xe2x80x9cY1Y2Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y1 and Y2 are as defined herein. Representative amino groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group. Representative alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group. Representative aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group. A representative aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cY1Y2NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y1 and Y2 are as defined herein. Representative carbamoyl groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY1Y2NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulfamoyl group, wherein Y1 and Y2 are as defined herein. Representative sulfamoyl groups are sulfamoyl (H2NSO2xe2x80x94) and dimethylsulfamoyl (Me2NSO2xe2x80x94).
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group. Preferred alkylsulfonyl groups are those in which the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group. Preferred alkylsulfinyl groups are those in which the alkyl group is lower alkyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-SOxe2x80x94 group.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
xe2x80x9cRing system substituentxe2x80x9d means a substituent that optionally replaces hydrogen on an aromatic or non-aromatic ring system. Ring system substituents are selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsultinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, 1-azaheterocyclylcarbonyl, Y1Y2Nxe2x80x94, Y1Y2N-alkenyl-, Y1Y2N-alkynyl-, Y1Y2NCOxe2x80x94, Y1Y2NCONHxe2x80x94, Y1Y2NCO2xe2x80x94Y1Y2NSO2xe2x80x94, wherein Y1 and Y2 are independently hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, provided that, when the substituent is Y1Y2Nxe2x80x94 or Y1Y2N-alkyl-, then one of Y1 and Y2 is acyl or aroyl and the other of Y1 and Y2 is hydrogen, alkyl, aryl, or aralkyl. When a ring system is saturated or partially saturated, the xe2x80x9cring system substituentxe2x80x9d is further selected from methylene (H2Cxe2x95x90), oxo (Oxe2x95x90) and thioxo (Sxe2x95x90).
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein the solvent molecules are H2O.
xe2x80x9cProdrugxe2x80x9d means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, the contents of which are hereby incorporated herein by reference.
xe2x80x9cAcid protecting groupxe2x80x9d means an easily removable group which is known in the art to protect an acid group against undesirable reaction during synthetic procedures and preferably to be selectively removable. The use of acid protecting groups is well known in the art for protecting carboxylic acid groups against undesirable reactions during a synthetic procedure, and many such protecting groups are known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. For suitable protecting groups, see T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991. Examples of carboxylic acid protecting groups include esters, such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, dialkylaminoalkyl (e.g., dimethylaminoethyl and the like), trimethylsilyl, and the like; C1 to C8 lower-alkyl (e.g., methyl, ethyl or tertiary butyl and the like); and amides and hydrazides, including N,N-dimethyl amide, 7-nitroindolyl hydrazide, N-phenylhydrazide; and benzyl and benzyl substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; alkanoyloxyalkyl groups such as pivaloyloxymethyl or propionyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxy-carbonylmethyl and the like; alkoxycarbonyloxyalkyl, such as t-butyloxycarbonyloxymethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocyclylcarbonyloxyalkyl, such as 4-methyl-piperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
xe2x80x9cAmine protecting groupxe2x80x9d means an easily removable group that is known in the art to protect an amino group against undesirable reaction during synthetic procedures and preferably to be selectively removable. The use of amine protecting groups is well known in the art for protecting amine groups against undesirable reactions during a synthetic procedure and many such protecting groups are known; see, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Preferred amine protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy, including methoxycarbonyl; 9-fluorenylmethoxycarbonyl; 2,2,2-trifluoro-ethoxycarbonyl; 2-trimethylsilylethxoycarbonyl; vinyloxycarbonyl; allyloxycarbonyl; tert-butoxycarbonyl (BOC); 1,1-dimethylpropynyloxycarbonyl; benzyloxycarbonyl (CBZ); p-nitrobenzyloxycarbony; 2,4-dichlorobenzyloxycarbonyl, and the like.
xe2x80x9cAcid labile amine protecting groupxe2x80x9d means an amine protecting group as defined above which is readily removed by treatment with acid while remaining relatively stable to other reagents. A preferred acid labile amine protecting group is tert-butoxycarbonyl (BOC).
xe2x80x9cHydrogenation labile amine protecting groupxe2x80x9d means an amine protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile amine protecting group is benzyloxycarbonyl (CBZ).
xe2x80x9cHydrogenation labile acid protecting groupxe2x80x9d means an acid protecting group as defined above which is readily removed by hydrogenation while remaining relatively stable to other reagents. A preferred hydrogenation labile acid protecting group is benzyl.
xe2x80x9cThiol protecting groupxe2x80x9d means a thiol protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of thiol protecting groups is well known in the art for protecting thiol groups against undesirable reactions during a synthetic procedure, and many such protecting groups are known; see, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Exemplary thiol protecting groups are trityl (Trt), acetamidomethyl (Acm), and the like.
xe2x80x9cHydroxy protecting groupxe2x80x9d means a hydroxy protecting group that is readily removed by some reagents while being relatively stable to other reagents. The use of hydroxy protecting groups is well known in the art for protecting hydroxy groups against undesirable reactions during a synthetic procedure, and many such protecting groups are known; see, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Exemplary hydroxy protecting groups are t-butyl, benzyl, tetrahydropyranyl, and the like.
Preferred Embodiments
A preferred embodiment of the invention is a method for treating a physiological condition capable of being modulated by inhibiting activity of Factor Xa by administering to a patient suffering from said physiological condition an effective amount of the compound of formula I.
A preferred embodiment of the invention is a method for treating a physiological condition capable of being modulated by directly inhibiting both Factor Xa and Factor IIa (thrombin), by administering to a patient suffering from said physiological condition an effective amount of the compound of formula I.
A preferred compound of the invention is a compound of formula I wherein n is 1.
A preferred compound aspect of the invention is a compound of formula I wherein W is H, lower alkyl, alkoxy, F or Cl.
A preferred compound aspect of the invention is a compound of formula I wherein R is aryl, heteroaryl or heterocyclyl; more preferably, R is substituted phenyl.
A preferred compound aspect of the invention is a compound of formula I wherein R is optionally substituted (phenyl substituted phenyl), optionally substituted (heteroaryl substituted phenyl), optionally substituted (phenyl substituted heteroaryl) or optionally substituted (heteroaryl substituted heteroaryl), (wherein the term xe2x80x9coptionally substitutedxe2x80x9d before the term in the parenthesis, denote that the phenyl or heteroaryl portions thereof could be further substituted as noted per their definitions).
A preferred compound of the invention is a compound of formula I wherein W=H.
Another preferred compound aspect of the invention is the compound of formula I wherein R8 is hydrogen.
Another preferred compound aspect of the invention is a compound of formula I wherein R2 and R3 taken together are xe2x95x90NR4.
Another preferred compound aspect of the invention is a compound of formula I wherein R4 is hydrogen or hydroxy; more preferably, R4 is hydrogen.
Another preferred compound aspect of the invention is a compound of formula I wherein R5 is alkyl; more preferably, R5 is methyl.
Another preferred compound aspect of the invention is a compound of formula I wherein both R6 and R7are hydrogen.
Another preferred compound of the invention is a compound of formula I wherein L1 is alkylene; more preferably, L1 is ethylene.
Another preferred compound aspect of the invention is the compound of formula I wherein L2 is alkylene-C(O)xe2x80x94 or alkylene-Oxe2x80x94.
Another preferred compound aspect of the invention is the compound of formula I wherein L2 is absent or alkylene.
Another preferred compound of the invention is a compound of formula I wherein L2 is absent.
Another preferred compound of the invention is a compound of formula I wherein X1 is O.
Another preferred compound aspect of the invention is a compound of formula I wherein Q is xe2x80x94NR8COxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR8SO2xe2x80x94 or xe2x80x94SO2NR8xe2x80x94; more preferably, Q is xe2x80x94NR8COxe2x80x94
Another preferred compound aspect of the invention is a compound of formula I wherein both R8 and R8xe2x80x2 are hydrogen.
Another preferred compound of the invention is a compound of formula I wherein m is 2.
Included within the scope of formula I are compounds wherein R2 and R3 taken together are xe2x95x90NR4, wherein R4 is R5O2Cxe2x80x94, R5Oxe2x80x94, cyano, R5COxe2x80x94, optionally substituted lower alkyl, nitro, or R6R7Nxe2x80x94. Such derivatives may themselves comprise the biologically active compound useful for treating a physiological condition capable of being modulated by inhibiting activity of Factor Xa by its administration to a patient suffering from said physiological condition, or may act as pro-drugs to such biologically active compounds which are formed therefrom under physiological conditions.
Individual compounds according to the invention include the following:
5-(Pyridin-2-yl)-thiophene-2-carboxylic acid (2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)amide;
4-tert-Butyl-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
4-(2-Amino-1,1-dimethylethyl)-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-4-(3-amino-propyl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-2-(N-phenyl-amino)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-2-(phenoxy)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-4-(N,N-diethylamino)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-4-(phenoxy)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-2-methyl-3-phenyl-prop-2-enoic acid amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-10-cyano-decanoic acid amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-4-oxo-(4-methoxy-phenyl)-butyramide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(1-methyl-pyrrole-2)-carboxamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(2,2-diphenyl)-propionamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(2-(4-chloro-phenoxy)-2-methyl-propionamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(2-[4-phenyl]-phenyl)-acetamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-3-[3,4-dimethoxy-phenyl]-prop-2-enoic acid amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(5-oxo-5-phenyl-pentanoic acid) amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-xanthine-9-carboxamide;
5-[1,2] dithiolan-3-yl-pentanoic acid-N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3ethyl]-amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-5-methoxy-indole-2 carboxamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-3,4-methylenedioxy cinnamic acid amide
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-3-quinoline carboxamide;
2,3-Dihydro-benzo[1,4]-dioxine-2-carboxylic acid-N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-(2-[4-cyano-phenoxy]-2-methyl-propionamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-2-(4-oxo-3,4-dihydro-pthalazin-1-yl)-acetamide;
3-Methyl-sulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]-thiophene-1-carboxylic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4,5-Dimethyl-1-phenyl-pyrrole-3-carboxylic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4-Oxo-4H-9-thia-1,4a-diaza-fluorene-3-carboxylic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
6-(1-pyrazole)-nicotinic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
3-Nitro-4-(1-pyrazolyl)benzoic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
N-Tosyl-3-pyrrole-carboxylic acid N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4-tert-butyl-2,6-dimethyl-cyclohexanecarboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
5-methyl-1-(3-trifluoromethyl-phenyl)-4,5-dihydro-1H-1,2,3-triazole-4-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
2-benzylsulfanyl-N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-propionamide;
5-pyridin-2-yl-thiophene-2-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4-butyl-cyclohexanecarboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-6-pyrrol-1-yl-nicotinamide;
4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid [2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-amide;
(S)-2-(6-Methoxynaphthyl)-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)propionamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)-3-chlorobenzothiophene-2-carboxamide;
4-Benzyloxy-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
4-(4-n-Propylphenyl)-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
2-Methylthio-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
3-(4-Pyridyl)-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)acrylamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)-4-tert-butylcyclohexanecarboxamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)-5-methylindole-2-carboxamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)quinoline-6-carboxamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzothiophene-2-carboxamide;
2-Pyrrolyl-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
4-Methyl-2-phenyl-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)-1,2,3-triazole-5-carboxamide;
N-(2-[5-Carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)-phthalide-3-acetamide;
N-(2-(5-Carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(phenyl)-benzamide;
N-[2-(5-Carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridin-3-yl)-benzamide;
4-(1-Aminomethyl-cyclopentyl)-N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridine-N-oxid-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridin-4-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-[(3-(aminomethyl)-phenyl]-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridazin-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyrimidin-5-yl)-benzamide;
N-[Biphenyl-4-yl-methyl]-2-(5-carbamimidoyl-2,3-dihydro-benzofuranyl) acetamide;
N-[Biphenyl-4-yl]-2-(5-carbamimidoyl-2,3-dihydro-benzoturanyl) acetamide;
3-(3-Biphenyl-4-ylmethyl-ureido-methyl)-2,3-dihydrobenzofuran-5-carboxamidine;
3-[2-(4-Benzyl-piperidin-1-yl-2-oxo-ethyl]-2,3-dihydro-benzofuran-5-carboxamidine;
3-{2-[4-(1,1-Dimethylpropyl)benzenesulfonylamino]ethyl}-5-carbamimidoyl-2,3-dihydrobenzofuran; and
3-[2-(7-Chlorobenzo[1,2,5]oxadiazole-5-sulfonylamino)ethyl]-5-carbamididoyl-2,3-dihydrobenzofuran.
More preferred species according to the invention are compounds:
5-(Pyridin-2-yl)-thiophene-2-carboxylic acid (2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)amide;
4-tert-Butyl-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
4-(2-Amino-1,1-dimethylethyl)-N-(2-[5-carbamimidoyl-2,3-dihydrobenzofuran-3-yl]ethyl)benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-benzofuran-3-yl)-ethyl]-4-(3-amino-propyl)-benzamide;
N-[2-(5-Carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(phenyl)-benzamide;
N-[2-(5-Carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridin-3-yl)-benzamide;
(1-Aminomethyl-cyclopentyl)-N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridine-N-oxid-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridin-4-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-[(3-(aminomethyl)-phenyl]-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridazin-3-yl)-benzamide;
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyridazin-4-yl)-benzamide; and
N-[2-(5-carbamimidoyl-2,3-dihydro-Benzofuran-3-yl)-ethyl]-4-(pyrimidin-5-yl)-benzamide.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
Compounds of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention as described herein.
As used herein the following reagents, solvents and terms are identified by the abbreviations indicated:
Acetic acid (ACOH or HOAc); acetic anhydride (Ac2O); acetamidomethyl (Acm); benzyl (Bn); t-Butoxycarbonyl (Boc); 2-(4-Biphenylyl)-prop-2-yl 4xe2x80x2-methoxycarbonylphenyl carbonate (Bpoc); benzyl carbamate (CBZ); n-butyl lithium (n-BuLi), cerium ammonium nitrate (CAN); cyclopropyl (Cp); 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); dichloromethane (DCM); diethylazodicarboxylate (DEAD); dicyclohexicarbodiimide (DCC); diisobutylaluminum hydride (DIBAL); N,N-Diisopropyl-carbodiimide (DIC), diisopropylethylamine (DIEA); N,N-dimethylaniline (DMA);
1,2-Dimethoxyethane (DME); N,N-dimethylformamide (DMF); diethyl azodicarboxylate (DEAD); 4-dimethylaminopyridine (DMAP); 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU); dimethylsulfoxide (DMSO); N-ethyloxycarbony-2-ethyloxy-1,2-dihydroquinone (EEDQ), equivalent (eq.); ethyl (Et); ethanol (EtOH); diethyl ether (Et2O); triethylamine (Et3N); ethyl acetate (EtOAc); 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride (EDC); hexamethylphosphoramide (HMPA); fast atom bombardment (FAB); 2-furanmethyloxycarbonyl (Foc), acetic acid (HOAc); high-performance liquid chromatography (HPLC); di-isopropylethylamine (Hunigs base); O-(7-azabenzotriazol-1-yl-1,1,3,3-tetramethylur onium hexafluorophosphate (HATU); O-(7-azabenzotriazol-1-yl-1,1,3,3-bis (tetramethylene uronium hexafluorphosphate (HApyU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(pentamethylene) uronium hexafluorophosphate (HApipU), O-(7-azabenzo-trizol-1-yl)-1,3-dimethyl-1,3-trimethylene uronium hexafluorophosphate (HAMTU); iso-propylacetate (iPrOAc); O-benzotriazolyl-1-yl-1,1,3,3-tetramethyluronium hexafluoro-phosphate(HBTU); 1-Hydroxybenzotriazole hydrate (HOBT); iso-propanol (iPrOH); potassium bis(trimethylsilyl)amide (KHMDS); lithium bis(trimethylsilyl)amide (LHMDS); methyl (Me); methanol (MeOH); m-chloroperoxybenzoic acid (MCPBA); methanesulfonyl chloride (mesyl chloride or MsCl); p-ethoxybenzyloxycarbonyl (Moz); sodium bis(trimethylsilyl)amide (NaHMDS); N-methylpyrrolidine (NMP); phenyl (Ph); Pyridine (Py); room temperature (r.t.); t-butyl methyl ether (TBME); benzotriazolyl-yl-1,1,3,3-bis (tetramethylene uronium tetrafluoroborate) (TBTU); 2-(trimethylsilyl)ethyl carbonate(TEOC); tetrahydrofuran (THF); trifluoroacetic acid (TFA); tetramethylethylene diamine (TMEDA); trimethylsilane (TMS); p-toluenesulfonyl chloride (tosyl chloride or TsCl); ); p-toluenesulfonic acid (TsOH); trityl (Trt), and p-toluenesulfonic acid (p-TSA).
The practice of this invention involves the synthesis of variously substituted dihydrobenzofurans and benzopyrans. In principle, this can be achieved by functionalization of specific precursors followed by ring synthesis or by derivatization of a preformed ring system. There are numerous approaches to the synthesis and functionalization of the aforementioned heterocycles in the chemical literature. For examples, see Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. Comprehensive Heterocyclic Chemstry II, Vol 2 and Vol 5. Elsevier Science 1996 and references cited therein. A particularly useful synthetic protocol with regard to the current invention is outlined in Scheme 1. 
In this approach, the requisite heterocyclic ring is constructed from a substituted phenol by (1) formation of an allylic-aryl ether. (2) Claisen rearrangement of this allylic ether to provide the corresponding olefin substituted phenol. (Lutz, R. P. Chem. Rev. 1984, 84, 205. In certain instances, it may be convenient to protect the phenolic hydroxyl with a temporary protecting group at this stage.) (3) Conversion of the olefin into an alcohol, alkyl halide or sulphonate. (4) Ring closure of the resulting product (after deprotection of the phenol where applicable).
Formation of an aryl allyl ether from a phenol can be effected using standard phenol alkylation conditions employing a base, such as sodium hydride THF, DME, DMPU, DMF, DMSO, HMPA or potassium carbonate, in a solvent such as THF, DME, DMPU, DMF, DMSO, HMPA, or a mixture thereof and an appropriate allylic halide or sulphonate. Alternatively, this transformation can be carried out by Mitsunobu etherification (Mitsunobu. O., Synthesis, 1981, 1) of a phenol with an appropriate allylic alcohol.
Synthesis of the requisite allylic alcohols/halides/sulphonates can be carried out using standard functional group transformations (see Larock, C. L. Comprehensive Organic Transformations, VCH Publishers 1989) such as outlined in Scheme 2. 
Conversion of an olefin into an alcohol can be carried out either by a standard hydroboration oxidation sequence (step 3a, Scheme 1). For examples, see (a) Beletskaya, I; Pelter, A. Tetrahedron, 1997, 53, 4957 and references cited therein; (b) Brown, H. C.; Kramer, G. W.; Levy, M. B.; Midland, M. M., Organic Synthesis via Boranes, Wiley Interscience, N.Y. 1973] or by oxidative cleavage of the olefin with a reagent such as ozone in dichloromethane followed by reduction of the resulting ozonide with sodium borohydride in methanol (step 3b, Scheme 1). In situations where the use of ozone is inconvenient, oxidative cleavage of the olefin linkage can also be effected with a reagent such as catalytic osmium tetroxide/sodium periodate in a solvent such as t-butanol/water or THF/water, at about room temperature. Conversion of an alcohol into the corresponding sulphonate can be carried out by treatment with, for example, toluenesulphonyl chloride/DMAP and a base such as triethylamine or diisopropylethylamine in a solvent such as dichloromethane, DMF or pyridine at or around room temperature. The corresponding halide can be installed by treatment of the alcohol with a reagent system such as NBS/Ph3P, NCS/Ph3P, I2/Ph3P/imidazole, CBr4/Ph3P. For a review, see Castro, B. R. Org. React., 1983, 29, 1). Ring closure can be effected on a phenol by Mitsunobu etherification or on a phenolic sulphonate or halide using the standard phenolic alkylation conditions described above.
Clearly, in situations where xe2x80x94Lxe2x80x94X is, or can be converted to, (CH2)nOH, this residue can also be used to effect ring closure (Scheme 1, step 5) and generate a heterocycle with an olefin side chain.
An alternative approach to benzopyrans and dihydrobenzofurans entails the use of an ortho-iodo-phenyl ether as a heterocyclic precursor (Scheme 3). Ring closure is initiated by metal halogen exchange using a reagent such as BuLi in THF or ether, generally at a low temperature, such as xe2x88x9278xc2x0 C. to xe2x88x92100xc2x0 C. The requisite aryl ethers for this approach can be prepared by alkylation of the ortho-iodo-phenol with a g-bromo but-2-enoate, such as methyl 4-bromo-crotonate, or by Mitsunobu etherification with a 5-hydroxy-pen-2-enoate (Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, Gian P. J. Mol. Catal. A: Chem., 1996, 111, 43). 
Ring closure of an iodo-alkene such as A (scheme 3) can also be effected under free radical conditions using a reagent such as tributyl tin hydride in a solvent such as benzene at a temperature above about 55xc2x0 C. in the presence of an initiator such as AIBN (2,2xe2x80x2-Azobixixobutyronitrile) or benzoyl peroxide.
The heterocyclic side chains incorporated as described above can contain, or be converted to, a variety of functional groups (using one or more steps) including amines, alcohols, aldehydes, ketones, carboxylic acids, esters, olefins, amides, imides, urethanes, carbamates, sulphonamides, sulphones, sulphoxides and sulfides. These interconversions employ standard synthetic methods described in the chemical literature. (For example, see Larock, C. L. Comprehensive Organic Transformations, VCH Publishers 1989 and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley Publications 1991). In particular, an alcohol in the side chain can be converted to the corresponding amine by a sequence (Scheme 4) involving (1) formation of a sulphonate or halide derivative as described above. (2) Reaction of this product with sodium azide in a solvent such as DMF, dimethyl acetamide, DMPU or ethanol at a temperature between 20 and 80xc2x0 C. and (3) reduction of the resulting azide with a reagent such as triphenylphosphine/water in THF or, alternatively, boron trifluoride etherate/1,3-propane-dithiol in a solvent such as dichloromethane. 
An amino functionality can also be introduced into the heterocycle side chain (Scheme 5) by conversion of an appropriate side chain alkene, first to an alcohol, using a hydoboration oxidation sequence, as previously described, then oxidation of the alcohol to the corresponding ketone using any of a number of common oxidation reagents such as Swern""s reagent. (For a review, see Hudlicky, T. Oxidations in Organic Chemistry, ACS Publications 1990). This is followed by reductive amination of the ketone (Abdel-Magid, A. F.; Maryanoff, C. A. Reductions in Organic Synthesis, ACS Symp. Ser., 641, p201, ACS Publications 1996) with an appropriate amine and a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a solvent such as methanol, THF, acetonitrile, HMPA, or water, either alone or as co-solvents. In certain cases, the amine functionality may be part of the heterocyclic side chain, in which case, a ring will be formed, which ring contains a secondary or tertiary amine). 
Another convenient method for introduction of an amino functionality into the side chain involves treatment of a side chain carboxylic acid with diphenylphosphoryl azide and a base, such as triethylamine or diisopropylamine, in a solvent, such as dichloromethane, THF, toluene or benzene, at a temperature usually between 0xc2x0 C. and room temperature. (For a review, see Banthrope, The Chemistry of the Azido Group, S. Patai Ed. Wiley Interscience N.Y. 1971.) Subsequent thermolysis of the resulting acyl azide (at room temperature to 140xc2x0 C.) in the presence of an alcohol, such as t-butanol, benzyl alcohol or allyl alcohol, provides the corresponding carbamate, which can be cleaved to the amine using standard protecting group chemistry. Thermolysis of the acyl azide in the absence of an alcohol produces the corresponding isocyanate, which can be reacted subsequently with a variety of amines to provide urethanes. (For a modification that also provides a convenient preparation of secondary amines, see Pfister, J. R.; Wymann, W. E. Synthesis, 1983, 38.) Alternatively, a urethane can be incorporated by reaction of a side chain amino functionality with an appropriate isocyanate. An imide functionality can be introduced by reaction of a side chain alcohol with a preformed, N-unsubstituted-imide using Mitsunobu""s reagent (Mitsunobu. O., Synthesis, 1981, 1) The imide, so formed, can also be converted to the corresponding amine by treatment with hydrazine in a solvent such as ethanol. Alternatively, the imide group can be introduced by acylation of a side chain amide with an acid choride (or an activated ester) in the presence of a base such as sodium hydride.
An amide linkage can be introduced into the heterocycle side chain by reaction of an amine (introduced using a method such as described above) with a carboxylic acid. Suitable conditions for effecting this transformation involve activation of the acid with a reagent, such as thionyl chloride, isopropyl chloroformate, oxalylchloride/DMF, TBTU, DCC, DICC/HOBT, CDI, BOP, EEDQ or PyBroP, usually in the presence of a base, such as triethylamine, diispropyl-ethylamine and/or DMAP. in a solvent, such as dichloromethane, DMF, dimethylacetamide or DMPU, at or above room temperature (For reviews see (a) Blackburn, C.; Kates, S. A. Methods Enzymol. 1997, 289, 175. (b) Bodanszky, M.; Trost, B. M. Principles of Peptide Synthesis 2nd Ed., Springer Verlag, N.Y. 1993). The reverse orientation of the amide unit can be prepared by reaction of an heterocycle side chain, containing an acid functionality, with an amine. An acid functionality can be formed in the side chain by oxidation of a side chain alcohol, first to the aldehyde, followed by oxidation of the aldehyde to the corresponding carboxylic acid. A particularly suitable reagent for this transformation is sodium chlorate (Lidgren, B. O.; Hilsson, T. Acta. Chem. Scand. 1973, 58, 238). Alternatively, an aldehyde can be generated by oxidation of an olefin, using osmium tetroxide with a co-catalyst, such as sodium periodate, in a solvent, such as THF/water or t-butanol/water. A carboxylic acid can also be obtained by cleavage of an appropriate ester according to standard protecting group methodology. A sulphonamide linkage can be introduced into the side chain by reaction of a side chain amino functionality with a sulphonyl chloride in the presence of a base, such as pyridine, triethylamine, diisopropylethylamine or sodium hydroxide, in a solvent, such as dichloromethane, pyridine, DMF or an alcohol such as ethanol or iso-propanol. The reverse orientation of the sulphonamide linkage can be produced by the method of Liskamp (Moree, W. J.; Van der Marel, G. A.; Liskamp, R. J. J. Org. Chem. 1995, 60, 1995) from a side chain thioacetate. The thioacetate functionality can be prepared by displacement of a halide or sulphonate with sodium thioacetate in a solvent, such as DMF, DMPU, HMPA or DMSO.
A sulphide linkage can be incorporated into the side chain by saponification of the thioacetate fuctional group, followed by alkylation of the resulting thiol with an appropriate alkyl halide or sulphonate (such as tosylate, triflate or mesylate). Alternatively, the sulphide linkage can be incorporated by direct reaction of a side chain alkyl chloride, bromide, iodide, tosylate or mesylate with a thiolate ion in a solvent, such as benzene, DMF, DMPU, HMPA or DMSO. In certain cases, a sulphide can be formed from an appropriate disulphide and a side chain alcohol in the presence of tributylphosphine in a solvent such as THF. The corresponding side chain sulphoxide and sulphone functionalities can be introduced by mild oxidation of the sulphides with an oxidizing reagent, such as m-chloroperbenzoic acid in dichloromethane chloroform or benzene at or below room temperature.
An ether linkage can be prepared from reaction of a side chain alcohol with an alkyl halide, sulphonate or xcex1,xcex2-unsaturated ketone and a base, such as sodium hydride potasium hydride, in a solvent, such as DMF, DMSO, THF, DMPU or HMPA (for a review see Comprehensive Organic Chemistry Vol 1, p 799, Ed. Barton, D.; Ollis, W. D., Pergamon Press, 1979). Alternatively, an ether linkage can be obtained using a side chain alkyl halide, sulphonate or xcex1,xcex2-unsaturated ketone and an appropriate alcohol under the same conditions. Another method of ether formation involves formation of a thiono-ester from a side chain ester or lactone by reaction with a thionating reagent, such as Lawesson""s reagent (for a review see Cava, M. P.; Levinson, M. I. Tetrahedron, 1985, 41, 5061), followed by reduction of the thiono group with a hydride reducing agent, such as tributyltin hydride, usually in the presence of a free radical initiater, such as AIBN.
Introduction of a nitrile can be achieved by conversion of an aldehyde to the corresponding oxime by reacting the aidehyde with hydroxylamine hydrochloride (Scheme 6) in a solvent, such as DMF, toluene or xylene, in the presence of a catalyst, such as toluene sulphonic acid and a desiccant, such as magnesium sulphate according to the method of Ganbao and Palomo (Ganbao, I.; Palomo, C. Syn. Commun. 1983, 13, 219. For alternatives to this procedure see Wang, E-C.; Lin, G-J. Tetrahedron Lett. 1998, 39, 4047 and references therein) The heating of the oxime with these reagents at a temperature between about 80xc2x0 C. and 150xc2x0 C. then results in dehydration to form the corresponding nitrile. 
Introduction of a nitrile group para to the oxygen functionality of the heterocyclic ring can be effected by a sequence (Scheme 7) involving treatment with bromine in a solvent, such as acetic acid or chloroform. The resulting aryl bromide can then be converted to the corresponding-cyano-derivative using zinc cyanide and a palladium catalyst, preferably tetrakis(triphenylphosphine) palladium(o) in DMF at a temperature between 70-90xc2x0 C. (Tschaen; D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.; King, S.; Verhoeven, T. R. Syn. Commun., 1994, 24, 887). This conversion can also be effected using copper cyanide in a solvent such as DMF, at elevated temperatures generally greater than 120xc2x0 C. (Ellis, G. P.; Romney-Alexander, T. M.; Chem. Rev., 1987, 87, 779). 
A particular embodiment of the current invention employs dihydrobenzofurans and benzopyrans substituted with a side chain that contains a bi-aromatic moiety, for example a biaryl, biheteroaryl, an aryl group substituted with a heteroaryl group, or an heteroaryl group substituted with an aryl group. bi-aromatic moieties can be prepared by cross coupling (Scheme 8) of an appropriately substituted aryl (or heteroaryl) halide or aryl (or heteroaryl) triflates with an aryl (or heteroaryl) organometallic (most commonly zinc, boron, magnesium or tin derivative) under catalysis by Pd(O) or Ni(O). For examples of such cross coupling reactions and conditions, see Tsuji, J. Palladium Reagents and Catalysts, J. Wiley Publications, 1996. 
Aryl and heteroaryl substituted heterocycles can also be prepared by direct ring synthesis. A wide variety of methods and conditions for this kind of process are known in the chemical literature (for example, see Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. Comprehensive Heterocyclic Chemstry II, Elsevier Science 1996).
In another embodiment of this invention the dihydrobenzofuran/benzopyran side chain contains a substituted aryl group. One particularly useful aryl group substituent comprises a 1,1-dimethyl alkyl chain (FIG. 1) further substituted with a heteroatom functionality (such as an amine, amide, sulphonamide, carbamate or urethane), a heteroatom cluster (such as a diol or amino-alcohol) or a heterocycle (such as imidazole). 
These systems can be prepared from 2-(4-furan-2-ylphenyl)-2-methylpropionic acid methyl ester, 2-(4-bromophenyl)-2-methylpropionic acid methyl ester (see experimental section) or 4-bromophenyl acetonitrile as shown in Schemes 9 and 10. Specifically, treatment of 2-(4-furan-2-ylphenyl)-2-methylpropionic acid methyl ester (1, Scheme 9) with methyl lithium in the presence of lithium hexamethyldisilazide, at or below room temperature, and reaction of the resulting enolate with TMS chloride provides the corresponding silyl enol ether. Reaction of this intermediate with 1 eq of bromine at low temperature (typically xe2x88x9278xc2x0 C.) furnishes the a-bromo-ketone (2). This compound can be treated with formamide at elevated temperatures (from about 50xc2x0 C.-180xc2x0 C.) to provide the corresponding imidazole (3). Alternatively, a-bromo ketone (2) can be reacted with sodium azide followed by reduction with sodium borohydride to provide the amino alcohol (5). After protection of the amino alcohol as a BOC derivative of the amine and a t-butyl di-methyl silyl ether (TBS ether) of the alcohol, the furan ring in (5) can be oxidatively cleaved to provide the benzoic acid derivative (6) using catalytic ruthenium trichloride/sodium periodate (a similar procedure can be used to prepare acid (4) from furan (3)). These benzoic acid units can then be attached to the dihydrobenzofuran or benzopyran scaffolds through amide bond formation as described above. 
Additionally, The methyl ester in (1) can be converted to an olefin of general formula (7) employing a sequence involving reduction with lithium aluminum hydride in a solvent such as THF or ether followed by oxidation of the resulting primary alcohol to the corrsponding aldehyde and Wittig or Horner-Emmons olefination (For a review see Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis, Academic Press, 1979). In the case of the olefin compound where Rxe2x95x90OMe, this system can be hydrolysed to the corresponding aldehyde with dilute HCl then oxidized to the carboxylic acid (8) as previously described. Amide formation on (8) produces (9) that can be further reacted with a reagent such as borane in THF to provide the amines (10). Subsequent oxidative cleavage of the furan ring in these systems, as described above, provides the acid functional group that is then coupled to the heterocyclic scaffold.
Alternatively, (Scheme 10) treatment of 2-(4-bromophenyl)-2-methylpropionic acid methyl ester (11) with diisobutylaluminum hydride at xe2x88x9278xc2x0 C. in dichloromethane followed by Swern oxidation of the resulting alcohol and Wittig reaction on the aldehyde provides the one carbon chain extended olefin (12). Osmylation of this species (12), followed by protection of the resulting diol as an acetonide (13) allows introduction of the carboxylic acid attachment point for coupling to the dihydrobenzofuran and benzopyran scaffolds. 
In addition, derivatized amine units such as (16) can be prepared from 4-bromophenyl acetonitrile (14) by a sequence involving methylation, then introduction of the furan to provide (15), reduction of the nitrile in (15) followed by amine derivatization with a carbonate, carboxylic acid, acid chloride, sulphonyl chloride or isonitrile and finally oxidative cleavage of the furan ring.
Certain preferred embodiments of this invention involve structures containing an amidine functional group. This group can be easily prepared from a nitrile (Scheme 11) employing a number of standard procedures. (for examples see Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala, T. E. Syn. Comm. 1996, 26, 4351 and references therein). In particular, treatment of the nitrile (17) with HCl in a solvent such as methanol or ethanol at a temperature at or above room temperature provides the imidate ester intermediate which can then be converted to the amidine (18) by treatment with ammonia or an alkylamine in a solvent such as methanol or ethanol. Alternatively, reaction of the nitrile with hydrogen sulphide in a solvent such as pyridine, followed by alkylation of the resulting thioamide with an alkylating agent such as methyl iodide in a solvent such as acetone at a temperature at or above room temperature and treatment of this product with ammonia or ammonium acetate in a solvent such as methanol at or above room temperature provides the final amidine (18). 
An amidine can also be prepared by addition of hydroxylamine to the nitrile to form the corresponding N-hydroxyamidine (19) followed by acylation and hydrogenolysis of the Nxe2x80x94O bond using hydrogen/acetic acid (AcOH)/acetic anhydride (AC2O) in the presence of a catalyst such as palladium on carbon.
For certain transformations of the side chain, it may be necessary or preferable to protect the amidine nitrogen as an inert derivative (Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts; John Wiley Publications 1991). A particularly suitable derivative for this purpose is the t-butyloxy-carbamate (20). This can be prepared by reaction of the appropriate amidine with di-t-butyldicarbonate in THF or dichloromethane in the presence of a base such as DMAP/triethylamine or disopropylethylamine at a temperature at or above room temperature. Cleavage of these BOC derivatives can be accomplished by treatment with trifluoro acetic acid (TFA) in dichloromethane or with HCl in ethyl acetate.
It will be apparent to those skilled in the art that certain compounds of formula I can exhibit isomerism, for example geometrical isomerism, e.g., E or Z isomerism, and optical isomerism, e.g., R or S configurations. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. Individual geometrical isomers and stereoisomers within formula I, and their mixtures, are within the scope of the invention.
Such isomers can be separated from their mixtures by the application or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or they can be separately prepared from the appropriate isomers of their intermediates, for example, by the application or adaptation of methods described herein.
The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
Where a compound of the present invention is substituted with a basic moiety, acid addition salts are formed, and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids that can be used to prepare the acid addition salts are preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on Factor Xa inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form, even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids, such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartarates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxy-naphthoates, gentisates, mesylates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution; or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be precipitated by concentration of the solution.
The parent compounds of this invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g., aqueous sodium bicarbonate solution or aqueous ammonia solution.
Where the compound of the invention is substituted with an acidic moiety, base addition salts thereof may be formed, and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts are preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on Factor Xa inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including, for example, alkali and alkaline earth metal salts, within the scope of the invention, are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
The parent compounds of this invention can be regenerated from the base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Pharmaceutically acceptable salts also include quaternary lower alkyl ammonium salts. The quaternary salts are prepared by the exhaustive alkylation of basic nitrogen atoms in compounds, including nonaromatic and aromatic basic nitrogen atoms, according to the invention, i.e., by alkylating the non-bonded pair of electrons of the nitrogen moieties with an alkylating agent such as methylhalide, particularly methyl iodide, or dimethyl sulfate. Quaternarization results in the nitrogen moiety becoming positively charged and having a negative counter ion associated therewith.
As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are most likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or wherein the compounds contain an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example, methods as described in the Reference Examples or their obvious chemical equivalents, or by methods according to this invention.
The present invention is further exemplified, but not limited, by the following illustrative examples, which illustrate the preparation of compounds according to the invention.
Experimental Section
Unless otherwise stated, all starting materials can be obtained from commercial suppliers and are used without further purification. Reactions are routinely carried out under an inert atmosphere of nitrogen or argon using anhydrous solvents obtained from Aldrich Chemical Company. Flash column chromatography is performed on Merck silica gel (230-400 mesh), eluting with the specified solvent mixture. Reverse phase HPLC is performed using Dynamax C-18 (60A) columns, eluting with a water/acetonitrile gradient (containing a fixed 0.1% v/v trifluoroacetic acid additive) with UV detection (xcex=220, 254, 294 nM). 1H NMR spectra are recorded at a frequency of 300 MHz in the specified deuterated solvent. Chemical shifts are in ppm relative to the resonance frequency of tetramethylsilane xcex4=0.00. The following conventions are used throughout to describe NMR spectra: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, b=broad. Coupling constants are designated with the symbol J and are quoted in Hz.